The family of natural products known as the schweinfurthins includes four compounds (FIG. 1, 1-4) isolated from the African plant Macaranga schweinfurthii Pax (see Beutler, J. A. et al., J. Nat. Prod. 1998, 61, 1509-1512; and Beutler, J. A., et al., Nat. Prod. Lett. 2000, 14, 349-404). Schweinfurthins A (1), B (2), and D (4) display significant activity in the NCI's 60-cell line anticancer assay with mean GI50's <1 μM. Their biological activity has attracted interest because some CNS, renal, and breast cancer cell lines are among the types most sensitive to these compounds. Inspection of the spectrum of activity shows no correlation with any currently used agents and suggests that these compounds may be acting at a previously unrecognized target or through a novel mechanism.
Repeated attempts to isolate larger samples of the schweinfurthins from natural sources have met with limited success; the absolute stereochemistry of these compounds has yet to be determined.
A cascade cyclization approach to the synthesis of racemic Schweinfurthin B was reported by E. Treadwell, et al., Organic Letters, 2002, 4, 3639-3642. The reported synthetic method, however, could not be elaborated to provide enantiomerically enriched mixtures of Schweinfurthin B.
Accordingly, there exists a need for synthetic methods that are useful for preparing enantiomerically enriched Schweinfurthin compounds. In addition to providing commercially useful quantities, such methods would allow sufficient quantities of the Schweinfurthin compounds to be prepared such that the absolute stereochemistry of the biologically active natural products can be determined. Additionally, general synthetic methods for preparing the Schweinfurthin ring structure would allow the preparation of structurally related compounds that might also have useful biological activity.